P699: MAGROLIMAB ALTERS THE TUMOR MICROENVIRONMENT TO IMPROVE BONE MARROW FUNCTIONS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) AND HIGHER-RISK MYELODYSPLASTIC SYNDROMES (HR-MDS)
Authors: Lisa Johnson, Yajia Zhang, Linda Su-Feher, Yeonju Lee, David A. Sallman, Adam S. Asch, Monzr M. Al Malki, Hyunjae Ryan Kim
Journal: HemaSphere (2023)

Background: Magrolimab (Hu5F9-G4) is a monoclonal antibody that blocks CD47, an antiphagocytic “don’t eat me” signal overexpressed on tumor cells. The demethylating agent azacitidine (AZA) increases expression of prophagocytic signals on the surface of tumor cells and acts synergistically with magrolimab to facilitate phagocytosis by macrophages. CD47 is a key negative regulator of innate immunity; therapeutic blockade of CD47 has the potential to trigger innate and adaptive immune antitumor activity within the bone marrow environment. Here, we used multiple approaches to gain comprehensive insight into the pharmacodynamic effects of magrolimab + AZA. Aims: To report the pharmacodynamic effects of magrolimab + AZA on the tumor microenvironment in patients with untreated HR-MDS or AML in a Phase 1b trial (NCT03248479). Methods: Patients with untreated HR-MDS or AML received magrolimab intravenously (IV) as a priming dose (1 mg/kg) on days 1 and 4, followed by a ramp-up to a 30-mg/kg weekly or biweekly maintenance dose. AZA 75 mg/m2 was administered IV or subcutaneously on days 1 to 7 of each 28-day cycle. Bone marrow aspirate and biopsies were obtained prior to the priming dose and at cycle 3 day 1 (C3D1). Soluble proteomic parameters were measured using slow off-rate modified aptamer (SOMAmer)–based technology. Stand-alone and integrated deep learning approaches using genomic, proteomic cell surface, transcriptomic and histopathologic data were used to gain comprehensive insight into the pharmacodynamic effects of magrolimab + AZA. Results: Immunohistochemistry showed a reduction in leukemic blasts at C3D1 in 17/22 (77%) patients with AML and 35/47 (74%) with HR-MDS. Among patients with MDS, a quantitative increase in the percentage of CD8+ T cells from baseline to C3D1 was observed in biopsies from 6/7 (86%) who achieved complete response (CR), 8/14 (57%) with mCR and 12/26 (46%) with either stable disease (SD) or disease progression (PD). In AML, there was an increase in CD8+ T cells in 7/9 (78%) biopsies from patients with CR, 2/3 (67%) with partial response (PR) and 60% (6/10) with SD. CD4+ T cells increased in 7/9 (78%) and 3/7 (43%) AML and MDS patients, respectively, who had CR; 3/3 (100%) AML patients with PR; 11/14 (79%) MDS patients with mCR; 5/10 (50%) AML patients with SD; and 14/26 (54%) MDS patients with SD or PD. Proteomics analysis showed 103 upregulated and 102 downregulated SOMAmer targets in AML (n=28) and 33 upregulated and 27 downregulated targets in HR-MDS (n=66). Many of the significantly changed SOMAmers were shared between AML and HR-MDS. Stand-alone and integrative analysis of copy number variation and mRNA differential expression profiles overlapped with the SOMAscan proteomic profile. Proteomic assessment and integrative profiles suggest a decrease in inflammation at C3D1, as evidenced by a decrease in proinflammatory proteins (eg, complement-C1q tumor necrosis factor–related protein 4) and an increase in the antitumor cytokine RANTES. Proteins associated with macrophages and other phagocytes were increased at C3D1 vs baseline. Summary/Conclusion: Patients treated with magrolimab + AZA demonstrated a shift in the bone marrow environment that is dominated by a phagocytic response, with evidence of adaptive immunity. As suggested by the mechanism of action, adaptive immunity was triggered via innate checkpoint inhibition. Additional deep learning approaches characterizing the tumor microenvironment in patients with HR-MDS and AML were also assessed and will be presented. Keywords: Myelodysplastic syndrome, Proteomics, Acute myeloid leukemia, Phagocytes